EP-A-622 361, WO 96-13485, and WO 96-40639, and the earlier priority, non-laid-open patent applications P 19610784.9 and P 19609827.0, disclose benzyloxy-substituted, fused N-heterocycles and their use as bradykinin antagonists.
The present invention relates to novel benzyloxy-substituted, fused N-heterocycles having high affinity for the bradykinin B.sub.2 receptor and improved pharmacokinetics.
The compounds according to the invention are described by formula (I) ##STR2##
in which the symbols have the following meanings:
D is a radical of formula (II) or (III): ##STR3## PA1 wherein: PA1 B is a radical of formula (VIII): ##STR4## PA1 R.sup.1 and R.sup.2, which may be identical or different, are PA1 R.sup.3 and R.sup.4, which may be identical or different, are PA1 R.sup.5 is PA1 R.sup.6, R.sup.8, and R'", which may be identical or different, are PA1 R.sup.7,R', and R", which may be identical or different, are PA1 R.sup.9 is PA1 A is a bivalent radical of an aminocarboxylic acid, such as methionine, alanine, phenylalanine, tyrosine, o-methylthyrosine, .beta.-(2-thienyl)alanine, glycine, cyclohexylalanine, leucine, isoleucine, valine, norleucine, phenylglycine, serine, cysteine, aminopropionic acid, or aminobutyric acid; PA1 Y is ##STR7## PA1 E is PA1 T is PA1 m and n, which may be identical or different, are each an integer from 0-6; PA1 o is an integer 0 or 1; PA1 R.sup.10 is PA1 R.sup.12 and R.sup.13, which may be identical or different, are PA1 R.sup.14 is PA1 R.sup.15 is PA1 R.sup.16 is PA1 with the proviso that in the case of compounds of formula (I) in which D is a radical of formula (II), R.sup.3 and R.sup.4 are not simultaneously halogen, (C.sub.1 -C.sub.3)-alkyl, and/or --O--(C.sub.1 -C.sub.3)-alkyl, or R.sup.3 and R.sup.4 are not hydrogen in combination with halogen, (C.sub.1 -C.sub.3)-alkyl, or --O--(C.sub.1 -C.sub.3)-alkyl; excluded from these are PA1 .alpha.. compounds of formula (I) in which D is a radical of formula (II) and R.sup.5 is a radical of formula (IV), wherein R.sup.10 is a heteroaryl group or a radical of formula (VI) ##STR8## PA1 wherein p is an integer from 1 to 3; and PA1 .beta.. compounds of formula (I) in which D is a radical of formula (II) and R.sup.5 is a radical of formula (V), for which, for its part, the proviso applies that R.sup.3 and R.sup.4 are not halogen. PA1 (A) compounds and salts of formula (I) in which D is a radical of formula (II), and R.sup.3 and R.sup.4 are simultaneously halogen, (C.sub.1 -C.sub.3)-alkyl, and/or --O--(C.sub.1 -C.sub.3)-alkyl; and PA1 (B) compounds and salts of formula (I) in which D is a radical of formula (II), and R.sup.3 and R.sup.4 are hydrogen in combination with halogen, (C.sub.1 -C.sub.3)-alkyl, or --O--(C.sub.1 -C.sub.3)-alkyl. PA1 (.alpha.) compounds and salts of formula (I) in which D is a radical of formula (II) and R.sup.5 is a radical of formula (IV), where R.sup.10 is a heteroaryl group or a radical of formula (VI) ##STR9## PA1 wherein p is an integer from 1 to 3, and R.sup.11 is: (a) a (C.sub.1 -C.sub.5) -alkyl, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine, or (b) a (C.sub.1 -C.sub.5)-alkoxy, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine; and PA1 (.beta.) compounds and salts of formula (I) in which D is a radical of formula (II) and R.sup.5 is a radical of formula (V). Of the compounds and salts included within the scope of the invention by proviso .alpha. above, however, the following compounds and salts are excluded from the scope of the invention: (i) compounds and salts where R.sup.10 has the formula (VI) and R.sup.3 and R.sup.4 are, identically or differently, hydrogen or halogen. Additionally, of the compounds and salts included within the scope of the invention by proviso .beta. above, the following compounds and salts are excluded from the scope of the invention: (ii) compounds and salts where R.sup.3 and R.sup.4 are halogen. PA1 X.sup.1 is --C--R.sup.6 ; PA1 X.sup.2 is --C--R.sup.7 ; PA1 X.sup.3 is --C--R.sup.8 ; PA1 R.sup.1 and R.sup.2, which may be identical or different, are PA1 R', R'", R.sup.6, R.sup.7, and R.sup.8, which may be identical or different, are PA1 R" is hydrogen; PA1 A is the bivalent radical of the amino acid glycine or alanine; ##STR10## PA1 Y is PA1 E is PA1 T is PA1 m and n, which may be identical or different, are each an integer from 0-3; p is an integer 1 or 2; PA1 R.sup.11 is PA1 R.sup.12 and R.sup.13, which may be identical or different, are PA1 R.sup.15 is PA1 and their physiologically tolerable salts; PA1 D is a radical of formula (II) or (III); PA1 B is a radical of formula (IX) ##STR11## PA1 X.sup.1 is --C--CH.sub.3 ; PA1 X.sup.2 is --C--H; PA1 X.sup.3 is --C--H; PA1 R' is methyl; PA1 R" is hydrogen; PA1 R'" is methyl; PA1 R.sup.1 and R.sup.2 are each hydrogen; PA1 R.sup.3 and R.sup.4, which may be identical or different, are PA1 R.sup.5 is. PA1 R.sup.9 is PA1 E is PA1 T is PA1 m and n, which may be identical or different, are each a number from 0 to 3; o is a number 0 or 1; PA1 R.sub.10 is PA1 R.sup.11 is PA1 R.sup.12 and R.sup.13, which may be identical or different, are PA1 R.sup.14 is PA1 R.sup.16 is PA1 with the proviso that in the case of compounds of formula (I) in which D is a radical of formula (II), R.sup.3 and R.sup.4 are not simultaneously chlorine, methyl, and/or O-methyl; excluded from these are PA1 .alpha.. compounds of formula (I) in which D is a radical of formula (II) and R.sup.5 is a radical of formula (X) wherein R.sup.10 is a heteroaryl group containing 4 to 7 carbon atoms in the ring structure or a radical of formula (VII) ##STR14## PA1 for which, for its part, the proviso applies that in the case of compounds of formula (I) in which the radical R.sup.10 has the formula (VII), R.sup.3 and R.sup.4 are not chlorine; and PA1 .beta.. compounds of formula (I) in which D is a radical of formula (II) and R.sup.5 is a radical of formula (V); for which, for its part, the proviso applies that R.sup.3 and R.sup.4 are not chlorine. PA1 a) reacting a compound of formula (XI) ##STR15## PA1 in which R.sup.1, R.sup.2, and D are as defined above for formula (I), in the presence of metal hydrides, such as lithium, potassium, or sodium hydride, or alkali metal carbonates, such as Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, or Cs.sub.2 CO.sub.3, in an inert solvent, such as DMF or DMSO, at temperatures from 0.degree. C. to 60.degree. C., preferably at room temperature, with a compound of formula (XII) ##STR16## PA1 in which R.sup.3 and R.sup.4 are as defined above in formula (I), to give a compound of formula (XIII) ##STR17## PA1 in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, and D are as defined above; PA1 b) reducing the compound of formula (XIII) with the aid of transition metal halides, preferably SnCl.sub.2 and FeCl.sub.3, to a compound of formula (XIV) ##STR18## PA1 in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, and D are as defined above; PA1 c) reacting the compound of formula (XIV) with activated, suitably protected aminocarboxylic acid derivatives of A ("A-Prot"), preferably the acid chlorides of the phthaloyl-protected aminocarboxylic acid derivatives of A, in inert solvents, such as CH.sub.2 Cl.sub.2 or N-methylpyrrolidone, if appropriate by addition of DMAP, in the presence of a base, such as pyridine, and thus obtaining a compound of formula (XV) ##STR19## PA1 in which A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and D are as defined above, and Prot is an amino-protective group, such as those described in T. W. Greene, "Protective Groups in Organic Synthesis", Verlag John Wiley, 2nd Edition 1991(suitable protective groups include, e.g., phthaloyl, benzyl, or paramethoxybenzyl); PA1 d) reacting the compound of formula (XV), after action of alkali metal hydrides, alkali metal carbonates or alcoholates, in inert solvents, preferably DMF or N-methylpyrrolidone, followed by a treatment with R.sup.9 X, wherein R.sup.9 is as defined above in formula (I) and X is a leaving group, e.g., halogen, mesylate, or tosylate, a compound of formula (XVI) being obtained ##STR20## PA1 in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, D, and A are as defined above and Prot is as defined in formula (XV); and PA1 e) converting the compound of formula (XVI) under suitable conditions into a compound of formula (XVII) shown below. This can be accomplished, for example, by hydrazinolysis in ethanol, in the case where a phthaloyl group is present as a protective group Prot, at a temperature from 20.degree. C. up to the boiling point, to thereby provide the compound of formula (XVII) ##STR21## PA1 in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, and D are as defined above, and A' is a radical of an aminocarboxylic acid. PA1 f1) reacting the compound of formula (XVII) with activated carboxylic acid and sulfonic acid derivatives R.sup.10 --E--Y--OH, in which R.sup.10, E, and Y are as defined above in formula (I), in conventional organic solvents, such as CH.sub.2 Cl.sub.2, dioxane, THF, or DMF, in the presence of an inorganic or organic base at a temperature from 0.degree. C. to reflux, to give a compound of formula (I), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, R.sup.10, A, D, and E have the above-mentioned meanings, B is a radical of formula (VIII), and R.sup.5 is a radical of formula IV, or PA1 f2) reacting a compound of formula (XVII) with an amine R.sup.10 --E--NH.sub.2, or an alcohol R.sup.10 --E--OH, preferably at a temperature from 0.degree. C. to room temperature, in inert solvents, such as dichloromethane or dimethoxyethane, to give a compound of formula (I), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, R.sup.10, A, D, and E have the above-mentioned meanings, B is a radical of formula (VII), and R.sup.5 is a radical of formula IV, where first, however, the compounds of formula (XVII) or the amine or the alcohol are allowed to react with a doubly activated carbonyl compound to form the urea or urethane group, e.g., with carbodiimides, phosgene, or chlorocarbonic acid esters, preferably phosgene and carbonyidiimidazole, or PA1 f3) reacting a compound of formula (XVII) with an appropriate isocyanate or isothiocyanate, preferably at a temperature from 0.degree. C. to room temperature, in inert solvents, preferably dichloromethane or dimethoxyethane, to give a compound of formula (I), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, R.sup.10, A, D, and E have the above-mentioned meanings, B is a radical of formula (VII), and R.sup.5 is a radical of formula IV. The following is the optional final step: PA1 g) optionally, converting the obtained compounds of formula (I), according to known methods, into their physiologically tolerable salts; PA1 A second process for making the compounds according to the invention is described below. PA1 a) reacting a compound of formula (XI) ##STR22## PA1 in which R.sup.1, R.sup.2, and D are as defined above for formula (I), in the presence of metal hydrides, such as lithium, potassium, or sodium hydride, or alkali metal carbonates, such as Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, or Cs.sub.2 CO.sub.3, in an inert solvent, such as DMF or DMSO, at a temperature from 0.degree. C. to 60.degree. C., preferably at 20 to 30.degree. C., with a compound of formula (XVIII) ##STR23## PA1 in which R.sup.3 and R.sup.4 are as defined above in formula (I), to give a compound according to formula (XIX) ##STR24## PA1 in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, and D are as defined above; PA1 b) reacting the compound of formula (XIX) in the presence of metal hydrides, such as sodium hydride, in inert solvents such as DMF, THF, or DMSO, with alkyl or aryl halides R.sup.9 -Hal, wherein R.sup.9 is alkyl or aryl as defined above and Hal is preferably iodide, at a temperature from 0.degree. C. to 40.degree. C., to produce a compound according to formula (XX) ##STR25## PA1 in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, and D are as defined above; PA1 c) treating the compound of formula (XX), first with an excess of acid, preferably trifluoroacetic acid, in the presence of a cation scavenger, such as anisole, for 4 to 24 hours at a temperature from 20.degree. C. to 60.degree. C. in an inert solvent, such as CH.sub.2 Cl.sub.2, and then reacting the compound obtained in the presence of an inorganic or organic base, such as Cs.sub.2 CO.sub.3 or NaH, with halides of formula Hal-R.sup.10, in which R.sup.10 has the meaning indicated above in formula (I), excluding hydrogen, to give compounds of formula (I), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, D, and R.sup.10 have the above-mentioned meanings, B is a radical of formula (VIII), and R.sup.5 is a radical of formula (V); and PA1 d) optionally converting the compounds of formula (I) thus obtained into their physiologically tolerable salts. PA1 1. Ligand: .sup.3 H-BRADYKININ (from NEN Du Pont) PA1 2. Buffer mixtures: PA1 3. Membrane preparation: PA1 4. Binding test: PA1 4. Assessment: PA1 5. Test results PA1 Amplifier: TF6 V3 Fleck, Mainz PA1 Pen recorder: Goerz Metrawatt SE 460, BBC PA1 Bradykinin: Bachem PA1 Thus, the compounds of Examples 6 and 20, for example, have the following IC.sub.50 values determined by the above procedure:
X.sup.1 is N or --C--R.sup.6 ; PA2 X.sup.2 is N or --C--R.sup.7 ; and PA2 X.sup.3 is N or --C--R.sup.8 ; PA2 1. hydrogen, PA2 2. halogen, or PA2 3. (C.sub.1 -C.sub.3)-alkyl; PA2 1. hydrogen, PA2 2. halogen, PA2 3. cyano, PA2 4. (C.sub.1 -C.sub.3)-alkyl, PA2 5. --O--(C.sub.1 -C.sub.3)-alkyl, PA2 6. --S--(C.sub.1 -C.sub.3)-alkyl, PA2 7. --OH, PA2 8. tetrazolyl, PA2 9. --CONHR.sup.9, or PA2 10. --COOR.sup.9 ; PA2 1. nitro, PA2 2. amino, PA2 3. a radical of formula (IV) ##STR5## PA2 4. a radical of formula (V) ##STR6## PA2 1. hydrogen, PA2 2. halogen, PA2 3. (C.sub.1 -C.sub.4)-alkyl, PA2 4. (C.sub.1 -C.sub.4)-alkoxy, PA2 5. amino, PA2 6. (C.sub.1 -C.sub.4)-alkylamino, PA2 7. hydroxyl, PA2 8. (C.sub.6 -C.sub.12)-aryl, PA2 9. (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkandiyl, or PA2 10. --CO.sub.2 R.sup.9 ; PA2 1. hydrogen, or PA2 2. (C.sub.1 -C.sub.4)-alkyl, PA2 1. hydrogen, PA2 2. (C.sub.1 -C.sub.4)-alkyl, PA2 3. (C.sub.2 -C.sub.5)-alkenyl, or PA2 4. (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.3)-alkandiyl; PA2 1. (C.sub.2 -C.sub.5)-alkenediyl, PA2 2. (C.sub.1 -C.sub.7)-alkanediyl, PA2 3. (C.sub.3 -C.sub.10)-cycloalkanediyl, or PA2 4. --(CH.sub.2).sub.m --T.sub.o --(CH.sub.2).sub.n --, wherein m, n, and o are defined such that --(CH.sub.2).sub.m --T.sub.o --(CH.sub.2).sub.n -- is not a (C.sub.1 -C.sub.7)-alkanediyl, PA2 1. O, PA2 2. S, or PA2 3. NR.sup.15 ; PA2 1. hydrogen, PA2 2. (C.sub.1 -C.sub.5)-alkyl, PA2 3. (C.sub.6 -C.sub.10)-aryl, PA2 4. (C.sub.1 -C.sub.3)-alkandiyl-(C.sub.6 -C.sub.10)-aryl-, or PA2 5. a heteroaryl group, PA2 1. hydrogen, PA2 2. (C.sub.1 -C.sub.5)-alkyl, PA2 3. (C.sub.2 -C.sub.5)-alkenyl, PA2 4. (C.sub.6 -C.sub.12)-aryl, PA2 5. (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.5)-alkandiyl, PA2 6. (C.sub.3 -C.sub.10)-cycloalkyl, PA2 7. (C.sub.3 -C.sub.10)-cycloalkyl-(C.sub.1 -C.sub.2)-alkandiyl, PA2 8. --C(O)--O--(C.sub.1 -C.sub.5)-alkyl, or PA2 9. --C(O)NH--(C.sub.1 -C.sub.5)-alkyl; PA2 1. hydrogen, PA2 2. --C(O)--O--(C.sub.1 -C.sub.4)-alkyl, or PA2 3. --C(O)--O--(C.sub.1 -C.sub.3)-alkyl-(C.sub.6 -C.sub.10)-aryl; PA2 1. hydrogen, PA2 2. --C(O)--(C.sub.1 -C.sub.3)-alkyl, or PA2 3. (C.sub.1 -C.sub.3)-alkyl; and PA2 1. (C.sub.1 -C.sub.3)-alkyl, PA2 2. (C.sub.6 -C.sub.12)-aryl, or PA2 3. a heteroaryl group, PA2 R.sup.11 is PA2 1. hydrogen, or PA2 2. methyl or ethyl; PA2 1. hydrogen, or PA2 2. (C.sub.1 -C.sub.4)-alkyl; PA2 1. (C.sub.2 -C.sub.5)-alkenediyl, PA2 2. (C.sub.1 -C.sub.7)-alkanediyl, or PA2 3. --(CH.sub.2).sub.m --T.sub.o --(CH.sub.2).sub.n --, wherein m, n, and o are defined such that --(CH.sub.2).sub.m --T.sub.o --(CH.sub.2).sub.n -- is not a (C.sub.1 -C.sub.7)-alkanediyl, PA2 1. O, or PA2 2. NH; PA2 1. --CF.sub.3, or PA2 2. --OCF.sub.3 ; PA2 1. hydrogen, PA2 2. (C.sub.1 -C.sub.5)-alkyl, PA2 3. (C6-C.sub.12)-aryl, or PA2 4. (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.3)-alkandiyl; PA2 1. hydrogen, or PA2 2. methyl or ethyl; PA2 1. chlorine, PA2 2. cyano, PA2 3. methyl, PA2 4. --O--methyl, PA2 5. --S--methyl, PA2 6. --OH, PA2 7. tetrazolyl, or PA2 8. --CONH.sub.2 ; PA2 1. nitro, PA2 2. amino, PA2 3. a radical of formula (X) ##STR12## PA2 4. a radical of formula (V) ##STR13## PA2 1. hydrogen, PA2 2. methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl, or PA2 3. benzyl; PA2 1. (C.sub.2 -C.sub.5)-alkenediyl, PA2 2. (C.sub.1 -C.sub.7)-alkanediyl, or PA2 3. --(CH.sub.2).sub.m --T.sub.o --(CH.sub.2).sub.n --, wherein m, n, and o are defined such that --(CH.sub.2).sub.m --T.sub.o --(CH.sub.2).sub.n -- is not a (C.sub.1 -C.sub.7)-alkanediyl group, wherein the radicals identified under 1-3 above are optionally substituted by a group selected from --OR.sup.12, --CO.sub.2 R.sup.9, --NR.sup.13 R.sup.14, or --CONR.sup.13 R.sup.14 ; PA2 1. O, or PA2 2. NH; PA2 1. hydrogen, PA2 2. (C.sub.1 -C.sub.5)-alkyl, PA2 3. phenyl, PA2 4. benzyl, or PA2 5. a heteroaryl group containing 4 to 7 carbon atoms in the ring structure, preferably furyl or pyridyl, PA2 1. --CF.sub.3, or PA2 2. --OCF.sub.3 ; PA2 1. hydrogen, PA2 2. methyl, ethyl, PA2 3. phenyl, or PA2 4. benzyl; PA2 1. hydrogen, PA2 2. --C(O)--O--C--(CH.sub.3).sub.3, or PA2 3. --C(O)--O--CH.sub.2 -phenyl; and PA2 1. methyl or ethyl, PA2 2. phenyl, or PA2 3. a heteroaryl group, wherein the ring structure contains 4 to 7 carbon atoms, PA2 a) TES buffer: PA2 b) Incubation buffer: PA2 a) Saturation experiments (hot saturation): PA2 b) Competition experiments (IC.sub.50): PA2 c) Screening:
wherein, in the radicals identified under 4, 5, and 6 above, 1 to 5 of the hydrogen atoms in the alkyl groups can be replaced by halogen atoms, PA3 wherein the radicals, identified under 1-4 above, optionally, can be substituted by one or more groups, such as --O--R.sup.12, --NO.sub.2, --CN, --CO.sub.2 R.sup.9, --NR.sup.13 R.sup.14, --SO.sub.3 R.sup.12, --SO.sub.2 NR.sup.13 R.sup.14 or --CONR.sup.13 R.sup.14 ; PA3 wherein radicals 3, 4, and 5 above can optionally be substituted by one or more groups, such as halogen, --CN, --NO.sub.2, (C.sub.1 -C.sub.5)-alkylthio, --NR.sup.13 R.sup.14, --NR.sup.13 CO--R.sup.16, --CO.sub.2 R.sup.9, --SO.sub.3 R.sup.12, --SO.sub.2 NR.sup.13 R.sup.14, --OR.sup.12, (C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.10)-aryl, (C.sub.2 -C.sub.5)-alkenyl, and (C.sub.1 -C.sub.5)-alkoxy, and wherein the last four PA3 radicals (i.e., the (C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.10)-aryl, (C.sub.2 -C.sub.5)-alkenyl, and PA3 (C.sub.1 -C.sub.5)-alkoxy radicals) can optionally be partially or completely substituted by halogen; PA3 wherein these radicals can optionally be substituted by one or more groups, such as halogen, --CN, --NO.sub.2, --NR.sup.13 R.sup.14, and --CO.sub.2 R.sup.9; PA3 1. (C.sub.1 -C.sub.5)-alkyl, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine, or PA3 2. (C.sub.1 -C.sub.5)-alkoxy, wherein the hydrogen atoms are partially or completely replaced by fluorine or chlorine; PA3 wherein the radicals identified under 1-3 above are optionally substituted by a group selected from --OR.sup.12, --NO.sub.2, --CN, --CO.sub.2 R.sup.9, --NR.sup.13 R.sup.14, --SO.sub.3 R.sup.12, --SO.sub.2 NR.sup.13 R.sup.14, or --CONR.sup.13 R.sup.14 ; PA3 wherein 3, 4, and 5 above can optionally be substituted by one or two groups selected from (C.sub.1 -C.sub.5)-alkyl, (C.sub.1 -C.sub.5)-alkoxy, --CF.sub.3, --OCF.sub.3, --NR.sup.13 R.sup.14, --NR.sup.13 CO--R.sup.16, and --CO.sub.2 R.sup.9 ; PA3 wherein these radicals can optionally be substituted by one or two groups selected from --NR.sup.13 R.sup.14 or --CO.sub.2 R.sup.9 ; PA3 25 mM TES (SIGMA, Order No.: T-4152) PA3 1 mM 1,10-phenanthroline (SIGMA; Order No.: P-9375) PA3 25 mM TES (SIGMA; Order No.: T-4152) PA3 1 mM 1,10-phenanthroline (SIGMA; Order No.: P-9375) PA3 0.1% albumin, bovine (SIGMA; Order No.: A-7906) PA3 140 .mu.g/ml bacitracin (SIGMA; Order No.: B-0125) PA3 1 mM dithiothreitol (SIGMA; Order No.: D-0632) PA3 1 .mu.M captopril-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline
wherein each R" in formula (III) may be identical or different;
and their physiologically tolerable salts;
for which, for its part, the proviso applies that when R.sup.10 has the formula (VI), R.sup.3 and R.sup.4 are not identically or differently hydrogen and halogen; and
To summarize, this invention relates to compounds according to formula (I) (and their physiologically tolerable salts), as defined above. Specifically, the invention includes the compounds and salts according to formula (I), except, the compounds and salts according to provisos (A) and (B) below are not included within the scope of the invention:
There are exceptions to the provisos (A) and (B) above. In particular, of the compounds and salts according to (A) and (B) which would be excluded from the scope of this invention by the terms of provisos (A) and (B), the following compounds and salts defined in (.alpha.) and (.beta.) are included within the scope of this invention:
Alkyl and alkenyl groups included in the compounds according to formula (I) can be straight-chain or branched. The same applies to radicals derived therefrom, such as, for example, alkoxy groups.
"Alkenyl" represents mono- or polyunsaturated radicals, such as 1,4-butadienyl and butenyl.
"Cycloalkyl" represents mono- or bicyclic radicals, such as cyclopropyl, cyclopentyl, cyclohexyl, and bicyclononyl. Likewise, "cycloalkenyl" represents mono- or bicyclic radicals, at least one of which includes a mono- or polyunsaturation.
A "(C.sub.6 -C.sub.12)-aryl" is, for example, phenyl, naphthyl, or biphenylyl, and preferably phenyl. The same also applies to radicals derived from aryl groups, e.g., in arylalkyl groups, the "aryl" represents, for example, phenyl, naphthyl, or biphenylyl, and preferably phenyl.
"Halogen" (or "Hal") represents fluorine, chlorine, bromine, or iodine, wherein chlorine or fluorine is preferred.
A "heteroaryl group" means a radical of monocyclic or bicyclic aromatic 5- and/or 6-membered ring systems which are derived from cyclopentadienyl, phenyl, indenyl, or naphthyl, wherein one or more CH-groups are replaced by N, NH, S, and/or O, and whereby the aromatic ring system is retained. In addition, one or both atoms of the condensation site of bicyclic radicals can also be nitrogen atoms, such as in indolizinyl. Generally, heteroaryl groups are ring structures containing five to ten ring atoms, one to nine of which are carbon atoms.
Examples of suitable heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzopyranonyl, coumarinyl, pyranonyl, and furandionyl.
All of the above-mentioned definitions also apply when these terms are used in connection with the corresponding bivalent radicals.
"Physiologically tolerable salts" of compounds of formula (I) are understood as meaning both their inorganic and organic salts, as are described in Remington's Pharmaceutical Sciences (A. R. Gennard Editor, Mack Publishing Co., Easton Pa., 17th Edition, page 1418 (1985). On account of their physiological and chemical stability and their solubility, acidic groups, such as, inter alia, sodium, potassium, calcium, and ammonium salts, are preferred; for basic groups, inter alia, salts of hydrochloric acid, sulfuric acid, or phosphoric acid, or of carboxylic acids or sulfonic acids, such as, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, and p-toluenesulfonic acid, are preferred.
Preferred compounds of formula (I) are those in which the symbols have the following meanings:
and the other radicals, variables, and provisos are as defined above for formula (I).
Particularly preferred compounds of formula (I) are those in which the symbols have the following meanings:
and their physiologically tolerable salts;
Very particularly preferred compounds of formula (I) are those in which D is formula (II) and the other radicals, variables, and provisos are as defined above for formula (I).
The invention additionally relates to processes for the preparation of compounds of formula (I). The first method is described below.
Method I:
The compound according to formula (XVII) is then reacted under suitable conditions to produce a compound of formula (I). Such conditions include:
Method II:
Processes for the preparation of the compounds of formula (XI) in which D is a radical of formula (VI) are known, inter alia, from H. Fiedler, J. Prakt. Chemie, Vol. 13, 1961, 86 ff.
Processes for the preparation of the compounds of formula (XI) in which D is a radical of formula (VII) are known, inter alia, from G. Gribble et al., Synthesis 10, (1975), pp. 650-652 and J. M. Schaus et al., Synth. Commun. 20, (1990), 3553-3562.
The conversion to the bromomethyl compound of formula (XII) or (XVIII) is carried out by reaction of the corresponding methyl derivative with N-bromosuccinimide or 1,3-dibromo-5,5-dimethyl hydantoin in inert solvents, preferably chlorobenzene or cyclohexane, at temperatures from 60.degree. C. up to the boiling point.
The replacement of chlorine by alkoxy or the corresponding S-alkylene is carried out by reaction with the corresponding alcoholates or thiolates, preferably their alkali metal or alkaline earth metal salts, in inert solvents between 0.degree. C. and 60.degree. C., preferably between 0.degree. C. and room temperature.
The cyano derivatives are prepared by substitution of chlorine by cyano by action of cyanides, preferably copper cyanide, in inert high-boiling solvents, such as DMF or N-methylpyrrolidone, at their boiling point.
The amide compounds result from the corresponding nitrile compounds by treatment with alkaline H.sub.2 O.sub.2 solution in alcoholic solution at temperatures from room temperature up to the boiling point.
The phenolic compounds result from the treatment of the corresponding alkoxy derivatives with Lewis acids, such as boron tribromide, in inert solvents at temperatures between 0.degree. C. and room temperature.
The methyl derivative of the compound of formula (XVIII) results from reaction of the corresponding sulfochloride derivative with t-butylamine in CH.sub.2 Cl.sub.2 at room temperature.
Additionally, it is noted that, inter alia, Examples 1a, 11a, 13b, and 16a below describe production of compounds of formula (XII), and Example 26 below describes production of a compound of formula XVIII.
Activated acid derivatives used in Method I, step f1, are acid chlorides, acid anhydrides, and active esters, e.g., carboxylic and sulfonic acid chlorides and bromides, mixed anhydrides, symmetrical anhydrides, p-nitrophenyl esters, and hydroxysuccinimide esters. The choice of one of these activated derivatives is dependent on the acyl or sulfonyl group to be introduced. In the case of the free carboxylic acids, the reaction is carried out in the presence of the condensing reagents used in peptide chemistry (see, for example, Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Vol. 15/2, Georg Thieme Verlag, Stuttgart, 1974), in particular carbodiimides such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide or chromium salts such as O-[cyano(ethoxy-carbonyl)methylenamino]-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (MBTU).
Individually or in combination, the compounds of formula (I) according to the invention have a bradykinin-antagonistic action which can be tested in various models (see the Handbook of Exp. Pharmacol., Vol. 25, Springer Verlag, 1970, pp. 53-55), for example, on the isolated rat uterus, on the guinea-pig ileum, on the isolated pulmonary artery of the guinea-pig, or on the jugular vein of the rabbit.
The effects of the compounds of formula (I) on bradykinin-induced bronchoconstriction and on carrageenin-induced paw edema can be determined in a manner analogous to the procedure described in the Br. J. Pharmacol., 102, 774-777 (1991).
The natriuretic and diuretic effect of the compounds of formula (I), including the compounds excluded therefrom under .beta., in chronic fibrogenetic liver disorders and acute liver disorders can be determined in the CCl.sub.4 -induced liver fibrosis model in the rat (see Bickel et al., J. Hepatol. (1991), 13 (Suppl. 3), S26-33).
The action of the compounds of formula (I), including the compounds excluded therefrom under .beta., on the cGMP production stimulated by the Alzheimer protein amyloid (.beta./A4) in isolated endothelial cells can be tested in the following manner:
Test Systems:
Bovine aorta endothelial cell cultures and microvascular coronary endothelial cell cultures
Method:
Determination of the effect of bradykinin receptor antagonists of formula (I) on the production of cGMP ("cyclic guanosine monophosphate") stimulated by administration of 1 .mu.mol/l of the Alzheimer protein .beta./A4 in endothelial cell cultures.
It has been adequately shown that endothelial cells are a suitable test system for the detection of an action and release of bradykinin (see G. Wiemer et al., Hypertension, 1991; 18: 558-563). In endothelial cells, bradykinin leads to an increase in the production of cGMP, which is determined by means of a radioimmunoassay. An increase in the formation of cGMP by bradykinin is an indicator of a release of NO (nitrogen monoxide) from endothelial cells.
Result:
The simultaneous incubation of the above-mentioned cell cultures with the compounds of formula (I), including the compounds excluded therefrom under .beta., in concentrations of 10 nM/l up to 10 .mu.M/l, prevents the stimulation of the production of cGMP induced by the .beta./A4 protein.
Assessment:
The experiment carried out indicates that the action of the Alzheimer protein .beta./A4 on the production of cGMP is mediated via binding of bradykinin to its cell receptors.
Endothelial cell cultures are used here as an indicator of an action of .beta./A4 which is mediated via bradykinin. The endothelial cells in this case, however, are not only the indicator system for an action via bradykinin receptors, but also the effector organ in Alzheimer's disease. Endothelial cells are constituents of the blood vessels and form these. The blood vessels themselves are severely affected by deposits of the Alzheimer protein amyloid (.beta./A4) in Alzheimer's disease in addition to neuronal tissue. Endothelial cells are responsible for an increase in the permeability of the blood-brain barrier caused by bradykinin.
The determination of the affinity of the compounds of formula (I) for the bradykinin .beta..sub.2 receptor was carried out on membrane preparations of the guinea-pig ileum (see R. B. Innis et al., Proc. Natl. Acad. Sci. USA, 17 (1981) 2630) according to the following procedure:
Both buffers are adjusted to pH 6.8 using 5 molar NaOH.
Guinea-pig ilea are grossly freed from intestinal contents by careful brushing and cleaned in 0.9% strength NaCl solution.
The pieces of ilea about 2 cm long are transferred to ice-cold TES buffer (about 1 g/10 ml) and homogenized in an ice bath for about 30 sec. using an Ultraturrax. The homogenate is then filtered through three layers of gauze, and the filtrate is centrifuged at 50,000 g/10 minutes.
The supernatant is discarded, and the pellet is rehomogenized in the same volume of TES buffer and centrifuged again at 50,000 g/10 minutes. The pellet is rehomogenized in incubation buffer (about 1 g/5 ml) and frozen at -70.degree. C. in cryotubes in 2 ml portions.
The protein concentration of the finished membrane suspension is determined according to LOWRY and should be about 15 .mu.g/100 .mu.l.
All incubations are carried out at room temperature for 60 minutes on microtiter plates (96.times.300 .mu.l) in a 200 .mu.l volume. All mixtures are in incubation buffer. To this end, 50 .mu.l of the radioligand, 50 .mu.l of the preparation to be tested, and 100 .mu.l of the membrane suspension are pipetted into the hollows of the microtiter plate in succession.
Preparation of the .sup.3 H-bradykinin solution: for the saturation experiments, the concentrations 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 2.0, 2.5, and 3.0 nmol/l are employed, which correspond to 0.05 to 3.0 pmol/ml. After the preparation of the appropriate dilutions, 50 .mu.l each are initially introduced per sample.
Nonspecific binding: for each concentration of the radioactive ligand, the nonspecific binding must be determined. This can be achieved by addition of a high concentration (1-100 .mu.mol) of the unlabeled ligand, other antagonists or agonists of the bradykinin receptor. In this test, HOE 140 (10 .mu.mol/l) is used. To this end, 1.862 mg are dissolved in 1 ml of dimethyl sulfoxide (DMSO), diluted 1:25 with incubation buffer, and 50 .mu.l of this solution are added to the samples in the microtiter plate. The reaction is started by the addition of 100 .mu.l of the membrane suspension.
Here a fixed quantity of the radioactive ligand (0.25 to 0.3 nmol/l of .sup.3 H-bradykinin) and various concentrations of the unlabeled agonists or antagonists are employed.
50 .mu.l of the preparations or standard to be tested in the concentrations 10.sup.-5 to 10.sup.-10 mol/l are added to 50 .mu.l in each case of the .sup.3 H-bradykinin solution, and the reaction is started by addition of 100 .mu.l of membrane suspension. Triplicate determinations also are carried out in this test, and three samples are incubated with 10 .mu.mol/l of HOE 140 to determine the nonspecific binding.
The preparations to be tested for competition are completely dissolved in a concentration of 1 mmol/l in dimethyl sulfoxide (DMSO), and then further diluted with DMSO. This solution is then diluted 1:25 with incubation buffer.
After the incubation, the samples are filtered off in a Skatron cell harvester through a Whatmann GF/B filter paper strip previously moistened with 0.1% PEI (polyethylenimine) and washed with 10 ml of ice-cold TES buffer per sample. The still moist filters are punched out into mini-scintillation tubes, and these are filled with 3 ml of scintillator.
After a soaking time of about 12 hours, the samples are briefly shaken and measured in a beta-counter.
In primary screening, in general only 1-2 concentrations of the test preparation (10.sup.-5 and 10.sup.-6 mol/l) are employed. If a displacement of the radioligand of 50% or more is detectable at the highest concentration, a complete analysis (competition experiment) is carried out using at least 8 concentrations.
Assessment is carried out by means of the LIGAND program package (McPherson, Minson & Rodbard, marketed by: Elsevier-BIOSOFT), which carries out the necessary calculations for the determination of IC.sub.50 and K.sub.i values. This program moreover carries out graphic presentations of the saturation or displacement curves as well as the SCATCHARD plot, HILL plot, or HOFSTEE plot.
According to the above-mentioned procedure, the following K.sub.i values were determined for the compounds of Examples 1, 6, 9, 16, 20, and 24, as described below, as representative compounds of the described benzyloxy-substituted, fused N-heterocycles of formula (I):
Example K.sub.i [nM] 1 8.3 6 0.1 9 6.0 16 17.4 20 5.4 24 1.0
In addition, for the determination of the bradykinin-antagonistic action of the compounds of fomula (I), their effect on the bradykinin-induced contraction of the guinea-pig ileum can be measured according to the following protocol:
Guinea-pigs about 300 g in weight (Morioth strain, .male..female.) are killed by a blow to the neck and exsanguinated. The ileum is dissected out in a length of about 20 cm, rinsed with Tyrode solution (Record Syringe), and thus freed from the intestinal contents. It is then divided into sections 1.5 cm long. These are fixed in organ baths of 10 ml capacity, which are filled with Tyrode solution, and connected to extension-measuring strips (isometric contraction measurement). The preload is 1 g. The Tyrode solution is warmed to 37.degree. C. in a water bath and bubbled through with compressed air. After an interval of 30 min, the experiment is begun. After recording the biological zero line, bradykinin in a final concentration of 4.times.10.sup.-8 mol/l is added per organ bath, and the concentration is recorded. Rinsing with Tyrode solution is then carried out for three min., and after a break of 20 min., bradykinin is again added. The maximum of the contraction is achieved (control). Rinse again, break. The bradykinin antagonist is then added (action time 10 min.). Bradykinin is then again added, and the contraction then taking place is compared with that of the control. The experiment is recorded on a pen recorder.
Tyrode solution (mM):
 NaCl 137 Glucose 5.05 KCl 2.68 NaHCO.sub.3 11.9 NaH.sub.2 PO.sub.4 0.47 MgCl.sub.2 .times. 2H.sub.2 O 0.49 CaCl.sub.2 .times. 2H.sub.2 O 0.68
 Example IC.sub.50 6 3.5 .times. 10.sup.-7 M 20 5.6 .times. 10.sup.-8 M
For the oral administration form or for application to the mucous membranes, the active compounds are mixed with additives customary for this purpose, such as excipients, stabilizers, or inert diluents, and are brought by means of customary methods into suitable administration forms, such as tablets; coated tablets; hard capsules; aqueous, alcoholic, or oily suspensions; or aqueous, alcoholic, or oily solutions. Inert carriers which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate, or starch, and in particular cornstarch. In this case, the preparation can be carried out both as dry and moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil and cod-liver oil.
A preparation for topical application can be present as an aqueous or oily solution, lotion, emulsion, or gel, ointment or fatty ointment or, if possible, in spray form, where adhesion can be improved, if appropriate, by addition of a polymer.
For the intranasal administration form, the compounds are mixed with additives customary for this purpose, such as stabilizers or inert diluents, and are brought by means of customary methods into suitable administration forms, such as aqueous, alcoholic, or oily suspensions or aqueous, alcoholic, or oily solutions. Chelating agents, ethylenediamine-N,N,N',N'-tetraacetic acid, citric acid, tartaric acid, or their salts can be added to aqueous intranasal preparations. The administration of the nasal solutions can be carried out by means of metered atomizers or as nasal drops having a viscosity-enhancing component or as nasal gels or nasal creams.
The compounds of formula (I) and their pharmacologically suitable salts are potent bradykinin antagonists. They can therefore be used for the treatment and/or the prevention of all pathological conditions which are mediated, caused or assisted by bradykinin and bradykinin-analogous peptides. This includes, inter alia, allergies, inflammations, autoimmune disorders, shock, pain, and, more especially, asthma, coughs, bronchitis, rhinitis, chronic obstructive pulmonary disorders, pneumonitis, septic shock, endotoxic shock, anaphylactic shock, disseminated intravascular coagulopathy, arthritis, rheumatism, osteoarthritis, lumbago, inflammation-induced bone resorption, conjunctivitis, iritis, headache, migraine, toothache, backache, cancer-related pain, postoperative pain, traumata (wounds, burns etc.), exanthema, erythema, edema, eczema, dermatitis, zoster, herpes, pruritus, psoriasis, lichen, inflammatory intestinal disorders, hepatitis, pancreatitis, gastritis, esophagitis, nutritional allergies, ulcers, irritable bowel, angina, cerebral edema, low blood pressure, thrombosis, cranio-cerebral and spinal trauma, premature birth, atherosclerosis, ascites in malignancy, tumor metastases, cerebral edema in tumors, heat injury to the brain, virus disorders, liver cirrhosis, and Alzheimer's disease.
The compounds of formula (I) excluded from the compounds of formula (I) under .beta. can likewise be used for the treatment and/or prevention of liver cirrhosis and/or Alzheimer's disease.
Since it is also known that bradykinin is linked with the release of mediators, such as prostaglandins, leukotrienes, tachykinins, histamine, and thromboxanes, the compounds of formula (I) thus also have the potential for treatment and/or prevention of the diseases which are caused by these mediators.
The invention therefore also relates to the use of compounds of formula (I) as therapeutics and to pharmaceutical preparations which contain these compounds.
Pharmaceutical preparations and therapeutics contain an effective amount of the active compound of formula (I)--individually or in combination--together with an inorganic or organic pharmaceutically utilizable carrier or excipient.
Administration can be carried out enterally, parenterally--such as, for example, subcutaneously, i.m., or i.v.--, sublingually, epicutaneously, nasally, rectally, intravaginally, intrabuccally, or by inhalation. The dose of the active compound depends on various factors, such as the warm-blooded species, the body weight, the age, and the manner of administration.
The pharmaceutical preparations of the present invention are produced in a dissolving, mixing, granulating, or coating process known per se.
For administration by inhalation, atomizers or compressed gas packs using inert carrier gases can be used.
For intravenous, subcutaneous, epicutaneous, or intradermal administration, the active compounds or their physiologically tolerable salts are brought into solution, suspension, or emulsion, if desired with the pharmaceutically customary auxiliaries, for example for isotonicization or pH adjustment, and solubilizers, emulsifiers, or other auxiliaries.
Should the half-lives of the described pharmaceuticals in body fluids be inadequate, the use of injectable delayed-release preparations is useful.
Pharmaceutical forms which can be used are, for example, oily crystal suspensions, microcapsules, rods, or implants, it being possible to construct the latter from tissue-compatible polymers, in particular biodegradable polymers, for example, those based on polylactic acid-polyglycolic acid copolymers or human albumin.
A suitable dose range for forms to be administered topically and by inhalation includes solutions containing 0.01-5 mg/l; in the case of systemic administration forms, dosages in the range of 0.01-10 mg/kg are suitable.
Generally, amounts between 0.1 and 1000 mg/kg of body weight can be administered.
List of abbreviations:
 abs. absolute BOC t-Butyloxycarbonyl CH.sub.2 Cl.sub.2 Dichloromethane DCI Desorption Chemical Ionization DMAP Dimethylaminopyridine DMF N,N-Dimethylformamide EA Ethyl acetate ESI Electron Spray Ionization FAB Fast Atom Bombardment M.p. Melting point satd saturated h hour(s) Hal Halogen MeOH Methanol min minute(s) RT Room temperature TOTU O-[Cyano(ethoxycarbonyl)methylenamino]-1,1,3,3- tetramethyluronium-tetrafluoroborate dec. decomposition